Rapid refeeding in anorexia nervosa: A dialectic balance

Abstract Objective To examine the impact of our new rapid refeeding protocol on patients with anorexia nervosa (AN) in our Eating Disorders Program. We hypothesize that the new protocol would lead to a more rapid weight gain and a shorter length of stay, with no effect on medical complications or program completion. Method This cohort design included consecutive inpatients and day hospital patients admitted to the program with a BMI <18 kg/m2 and a diagnosis of AN between 2007 and 2020; N = 326 patients. Main outcomes measured were rate of weight gain and length of stay. Safety indicators included electrolyte disturbances and supplementation required, complications including refeeding syndrome and completion of the program. A p value <.05 was considered statistically significant. Results Total length of stay was 21 days shorter for patients on the rapid refeeding protocol compared to the traditional refeeding protocol. Patients on the new protocol gained 0.21 more kg/week compared to patients on the old protocol. There was no difference in completion rates between programs. Electrolyte imbalances were mild to moderate and easily treated with oral electrolyte supplementation. There were no deaths or cases of refeeding syndrome with either protocol. Discussion This is the first Canadian study to assess the effectiveness and safety of rapid refeeding in an adult population. Rapid refeeding protocols can be safely administered and are cost effective. Shorter hospital admissions are desirable to minimize possible regression and dependency on inpatient services and positively impacts patients' quality of life. Public Significance This study advances the idea that rapid refeeding in patients with anorexia nervosa can be administered safely and effectively with close medical monitoring. In addition, rapid refeeding leads to shorter hospital stays, with a cost‐savings to the health system. Shorter admissions are desirable to minimize possible regression and dependency on inpatient services and also positively impacts patients' quality of life.


| INTRODUCTION
tious approach to refeeding due to fears of refeeding syndrome, are outdated. However, several studies published between 2010 and 2021 have adopted a more rapid refeeding approach to AN with good results (Garber et al., 2012(Garber et al., , 2013Gentile et al., 2010;Golden et al., 2013;Haynos et al., 2016;Koerner et al., 2020;Leclerc et al., 2013;Madden et al., 2015;Parker et al., 2016;Pettersson et al., 2016;Redgrave et al., 2015;Rigaud et al., 2007;Smith et al., 2016;Whitelaw et al., 2010). The treatment of AN needs to balance the urgent need for weight restoration and nutritional rehabilitation while also minimizing the medical risks of refeeding. Several published case reports of refeeding syndrome between 1980 and 2000 were influential in establishing cautious and conservative recommendations for nutritional rehabilitation in AN (Beumont & Large, 1991;Fisher et al., 2000;Kohn et al., 1998;Norris et al., 2012;Weinsier & Krumdieck, 1981). The unpredictable nature and presentation of refeeding syndrome coupled with limited controlled trials have likely perpetuated a cautious approach to refeeding in the field of Eating Disorders.
Refeeding syndrome is a complex, potentially lethal metabolic disorder which can occur during the early stages of refeeding a very malnourished individual. The main biochemical marker is low phosphate, but refeeding syndrome can also lead to low potassium, sodium, magnesium, thiamine, abnormal liver enzymes, hemolytic anemia, high glucose, and abnormalities in white blood cells leading to impaired chemotaxis and abnormal phagocytosis (Society for Adolescent Health and Medicine, 2014). Numerous body systems can be negatively affected leading to neurological, cardiac, and respiratory complications, end-organ damage, and sudden death within a few days to weeks of increasing caloric intake (Hearing, 2004; Society for Adolescent Health and Medicine, 2014). Refeeding hypophosphatemia and cardiac and neurological events usually develop within the first 7-10 days of nutritional rehabilitation (Matthews et al., 2018;Parker et al., 2016). Refeeding syndrome can be defined by three criteria: (1) severely low electrolytes, (2) peripheral edema or acute circulatory fluid overload, and (3) disturbance to organ function including respiratory failure, cardiac failure, and pulmonary edema (Parker et al., 2016;Rio et al., 2013). Several authors have questioned whether refeeding syndrome is even preventable by caloric manipulation (Garber et al., 2016;Kohn et al., 1998;O'Connor & Goldin, 2011;Society for Adolescent Health and Medicine, 2014). However, the severity of malnutrition pretreatment seems to be a more important risk factor for refeeding hypophosphatemia, rather than the energy intake or rate of weight gain during treatment (Haynos et al., 2016;O'Connor & Nicholls, 2013;Ornstein et al., 2003;Parker et al., 2016;Redgrave et al., 2015). Review papers in the field of Eating Disorders have reported an average incidence of hypophosphatemia of 14%, with observed rates as high as 37%-45% (Garber et al., 2012;Leitner et al., 2016;Norris, 2016;Redgrave et al., 2015 On the slower traditional refeeding protocol, patients were usually started on 1500-1600 kcal/day and were gradually increased by 300 kcal once a week up to a maintenance level of 2100-2300 kcal using the Harris Benedict Equation with a stress factor of 1.6 to account for higher metabolic needs. This calorie level was maintained as long as patients were gaining greater than 1 kg/week. If patients failed to gain 1 kg, then their prescribed meal plan would increase by 300 kcal/week. Patients in our older protocol were weighed once a week and meal plans were only increased once a week. . In our rapid refeeding protocol, patients were started on 1600-1800 kcal/day and were increased by 600 kcal/week to 2800 kcal/ day by day 21, regardless of weight gain in the first few weeks. After 2800 kcal/day, if patients failed to gain 1 kg/week their meal plans were increased by another 300-400 kcal/day every week in collaboration with our program dietician.
The primary aims of our study were to examine the effect of our institutional change in refeeding protocol on the rate of weight gain, and length of stay in our inpatient and day program. Secondary aims of the study were to look at safety indicators such as electrolyte disturbances and supplementation, refeeding syndrome, transfer to an internal medical ward, deaths, and completion of the program.
We hypothesized that the change in our refeeding protocol would lead to more rapid weight gain and a shorter length of stay, with no increases in medical complications or program drop-outs.

The project was determined by the Research Ethics Board at Trillium
Health Partners to not be human subject research requiring REB review and oversight. We followed a natural experimental design comparing patients with AN admitted to our Eating Disorder Program before and after an institutional change in our refeeding protocol. We included all consecutive inpatients and day hospital patients admitted to the CVH Eating Disorders Program with a BMI less than 18 kg/m 2 and a diagnosis of AN between May 7, 2007 and December 31, 2020.
Patients were excluded from the review if they had a diagnosis of Avoidant Restrictive Food Intake Disorder, Eating Disorder Not Otherwise Specified, or bulimia nervosa. Patients were also excluded if their inpatient or day hospital stay was less than 7 days, or if they required naso-gastric tube feeding or a modified meal plan based on other medical diagnoses ( Figure 1). Data were collected retrospectively for patients admitted on the slow refeeding protocol and obtained prospectively for patients admitted on the rapid refeeding protocol. All inpatients were weighed routinely by nursing staff using a consistent method in a gown, with a medical Healthometer Professional electronic scale. We obtained data on each patient's age, sex, admission and discharge weights, rate of weight gain, number of days on the weight gain protocol, target weight, length of stay, rate of completion, reason for premature discharge, and days until target BMI was achieved.
We obtained measures of inorganic phosphorus, potassium, and magnesium levels for inpatients. For laboratory values, we report total numbers and percentages of those with each of the laboratory abnormalities. Group means, SDs, medians, and ranges of these values are reported. Hypophosphatemia was considered present when levels fell below the reference range Demographic and clinical data are presented as means and SDs, medians and interquartile ranges (IQR), and counts and percentages as appropriate. Q-Q plots and results of Shapiro-Wilk tests were examined to assess the underlying distribution of continuous outcomes. Rate of weight gain was reported as kg/week, and days to reach a target BMI of 19.5 kg/m 2 was reported as a mean with SD. Student's t-tests and Wilcoxon rank sum tests were

| RESULTS
A total of 326 inpatients with AN were assessed between 2007 and 2020. Table 1 shows the baseline characteristics of patients who were enrolled in the slow refeeding program from 2007 to 2016 and the new rapid refeeding program from 2017 to 2020. There were no statistically significant differences between the two cohorts.
When examining the inpatient program, the mean weight and mean BMI at inpatient discharge were not significantly different between patients in either cohort ( Table 2) There were no differences in weight gain, BMI at discharge or program completion rates between the day hospital (DH) cohorts ( Following adjustment for admission diagnosis, on average, the total length of stay was 22 days shorter among patients in the new protocol and these patients gained 0.21 more kg/week in the new program compared to the old program (Table 5).
Hypophosphatemia was not significantly different between the slow and rapid refeeding protocols after admission ( There were more low magnesium values after admission in our older, slower refeeding protocol than the new rapid protocol; however, this was not statistically different. The severity of the hypomagnesemia did not differ, and the vast majority were mild/moderate cases. There were more low potassium levels recorded at any point after admission with the new rapid protocol compared to the old protocol. This finding may in part be due to the fact that more patients entered the program with low admission potassium levels. However, the severity of low potassium did not differ between groups after admission (Table 6), and the vast majority were of mild severity treated with oral supplementation (Table 7).
Among patients who experienced low magnesium and potassium levels after admission, the median number of days to nadir was not different between the traditional and rapid programs across all three electrolyte groups.
The amounts of phosphate supplements used to treat phosphate deficiencies were higher in the slow protocol compared to the rapid protocol. The amounts of potassium and magnesium supplements used did not differ between cohorts (Table 7). An admission BMI less than 14 kg/m 2 was associated with a 2.76 times higher odds of experiencing low phosphate after admission compared to patients with a BMI greater than/equal to 14 kg/m 2 .
There were no deaths or cases of refeeding syndrome that met all three diagnostic criteria (Rio et al., 2013) with either protocol over the 14-year period. Four patients on the slow refeeding protocol and one patient on the rapid refeeding protocol were transferred from our Eating Disorders unit to a medical ward for medical instability not related to refeeding.

| DISCUSSION
This is the first publication to assess the effectiveness and the safety of rapid refeeding in an adult population in Canada. This study adds to the growing body of literature demonstrating that rapid refeeding protocols can be safely administered, are cost effective, and preferable in many ways (Garber, 2020;Haynos et al., 2016;Redgrave et al., 2015).
This study provides evidence that more rapid weight gain is possi-  atrists, 2014). This study in combination with others over the last 8 years challenge the "start low, go slow" paradigm of refeeding in AN. There has been increased recognition over the last 5 years that slow, "underfeeding" in AN treatment can have detrimental effects on weight gain, cognition, blood sugars, organ damage, cardiac abnormalities, early weight loss in treatment, and hospitalization, contributing to a worse outcome (Garber et al., 2016;Koerner et al., 2020). Given that a slower rate of weight gain in hospital and day program treatment has been associated with a worse outcome in AN (Castro et al., 2004;Chatelet et al., 2020;Garber et al., 2016;Golden et al., 2013;Lund et al., 2009;Smith et al., 2016;Steinhausen et al., 2008;Zipfel et al., 2000), it is imperative that patients are given enough calories to efficiently restore both physical and mental health in a timely manner (Golden et al., 2013;Lund et al., 2009;Sly & Bamford, 2011;Steinhausen et al., 2008). Our traditional, slow refeeding protocol often resulted in weight loss in the first 1-2 weeks of treatment, because initial calorie prescriptions were typically below resting energy requirements (Garber et al., 2012;Kohn et al., 2011).
Patients with AN become hypermetabolic during the refeeding process, which can substantially increase calorie requirements and hinder weight gain (Garber et al., 2012;Pettersson et al., 2016). A faster rate of weight gain in treatment is desirable to rapidly improve cognitive functioning so that patients are more able to engage in meaningful psychotherapy, CBT, and DBT skills, which are essential for a durable, lasting recovery. Even the best therapies will not be effective in the face of malnutrition, low blood sugars, and cognitive impairment. Our rapid refeeding protocol allowed our dietician to introduce more variety into our patients' meal plans earlier in treatment, allowing for more exposure and desensitization to challenging "risk" foods on their hierarchy.
Our rapid refeeding protocol resulted in a decreased overall length of stay of 21 days in patients who completed the entire program using the rapid refeeding protocol. Length of inpatient stay decreased from an average of 53 to 40 days, and in Day Hospital from 52 to 44 days, an overall decrease of 25% and 15%, respectively.

Given the limited resources and long waiting lists for intensive Eating
Disorder services, the decrease in length of stay is both statistically and clinically significant. The cost to treat AN is among the highest of all psychiatric disorders due to the extensive use of hospital services (Bulik et al., 2007). A 13-day decrease in length of inpatient stay amounts to a cost savings of $7748 per patient, and would allow our four bed inpatient unit to treat an extra 10-13 patients per year and decrease our waiting list. Over the 9 years of utilizing the slow refeeding protocol, the program averaged 26.7 admissions per year.
The new rapid refeeding program averaged 40 admissions per year; providing care to an additional 13.2 patients per year. A shorter hospital admission is further desirable to minimize possible regression and dependency on inpatient services, and to achieve more skill generalization in the patients' usual home environment. A shorter stay also positively impacts the patients' quality of life by minimizing disruption to a patient's school, work, family, and social life (Castro et al., 2004). and magnesium occurred in our study, they were usually mild in severity and easily treated with oral supplements.
We believe that concerns of refeeding syndrome and refeeding hypophosphatemia have been overstated. Over 18 published studies to date have used a rapid refeeding approach to varying degrees in adults and adolescents with a total sample size of 1632. Of these studies, none have reported cases of refeeding syndrome or deaths due to refeeding (Agostino et al., 2013;Garber, 2020;Garber et al., 2012Garber et al., , 2013Gaudiani et al., 2012;Golden et al., 2013;Haynos et al., 2016;Koerner et al., 2020;Leclerc et al., 2013;Madden et al., 2015;Matthews et al., 2018;Parker et al., 2016;Pettersson et al., 2016;Redgrave et al., 2015;Rigaud et al., 2007;Smith et al., 2016;Whitelaw et al., 2010). In fact, most case reports of refeeding syndrome in the literature have occurred in patients with AN who were treated with a slow, traditional, refeeding protocol (Kohn et al., 1998;O'Connor & Goldin, 2011). Increased rates of refeeding hypophosphatemia are associated with lower BMI and more severe emaciation at admission, but not with the rate of refeeding or rates of weight gain (Garber et al., 2013(Garber et al., , 2016Leitner et al., 2016;Ornstein et al., 2003;Parker et al., 2016;Redgrave et al., 2015 There are several limitations to this study. This was a single-sited nonrandomized controlled study and some data points were collected retrospectively, which relied on complete data being present in patient charts. We collected and analyzed laboratory values for inpatient records only; laboratory data were insufficient to make meaningful comparisons or conclusions for day hospital patients. Data on the number of days to reach the target BMI of 19.5 kg/m 2 were limited to 105 patients in the old program and 45 patients in the new, as a significant number of patients attended a residential or day program closer to their home to complete weight restoration and recovery.
Although significant associations between the slow and rapid refeeding programs and two primary outcomes were noted, we also observed low precision around the estimates, which may suggest the need for a larger sample. We did not examine the long-term outcomes for patients, which would be important to look at in future studies.
Finally, there is risk of maturation bias, as practices evolve over the passage of time and may influence the study outcomes. There were no intentional changes made to our program and psychotherapies during this time.
Historically, Eating Disorder clinicians would endeavor to strike a balance between the benefits of rapid weight gain and medical stabilization against the risk of refeeding syndrome.
Given that the risk of refeeding syndrome is rare and was not present in over 18 published studies involving over 1632 patients using a more rapid protocol, it is time that the pendulum swings to a more rapid, assertive approach to refeeding (Golden et al., 2013). Our analysis suggests that initial calorie prescriptions and increases can safely exceed the current recommended guidelines and concerns of refeeding syndrome and refeeding hypophosphatemia are likely overstated. More aggressive refeeding protocols should be implemented with close medical monitoring and prompt treatment of electrolyte abnormalities with supplements to mitigate any potential risks of refeeding syndrome. Given that faster weight gain in both inpatient and outpatient ambulatory settings has been associated with higher weight at discharge and similar outcomes at 1-year follow-up (Chatelet et al., 2020;Garber et al., 2016Garber et al., , 2021, it is important to speed up the process of nutritional rehabilitation while patients are in a safe and supervised environment. Shorter hospital admission followed by intensive residential and day hospital treatments have not been found to be detrimental to long-term outcomes in AN (Smith et al., 2016). Our study adds to a growing body of literature that argues that the risks of underfeeding syndrome are greater and more common than refeeding syndrome in specialized settings for the treatment of AN.